Synergistic insights into human health from aptamer- and antibody-based proteomic profiling.

Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques-the aptamer-based SomaScan® v4 assay and the antibody-based Olink assays-to systematically assess phenotypic consequences of hundreds of pQTLs discovered for 871 protein targets across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein-phenotype connections, 36.3% of which were only seen with one of the two platforms suggesting that both techniques capture distinct aspects of protein biology. We further highlight discordance of genetically predicted effect directions between assays, such as for PILRA and Alzheimer's disease. Our results showcase the synergistic nature of these technologies to better understand and identify disease mechanisms and provide a benchmark for future cross-platform discoveries.

Genetic architecture of host proteins involved in SARS-CoV-2 infection.

Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).

Genetic architecture of host proteins interacting with SARS-CoV-2.

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid 'in silico' assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).

The Impact of the Glomerular Filtration Rate on the Human Plasma Proteome.

PURPOSE: The application of proteomics in chronic kidney disease (CKD) can potentially uncover biomarkers and pathways that are predictive of disease. EXPERIMENTAL DESIGN: Within this context, this study examines the relationship between the human plasma proteome and glomerular filtration rate (GFR) as measured by iohexol clearance in a cohort from Sweden (n = 389; GFR range: 8-100 mL min-1 /1.73 m2 ). A total of 2893 proteins are quantified using a modified aptamer assay. RESULTS: A large proportion of the proteome is associated with GFR, reinforcing the concept that CKD affects multiple physiological systems (individual protein-GFR correlations listed here). Of these, cystatin C shows the most significant correlation with GFR (rho = -0.85, p = 1.2 × 10-97 ), establishing strong validation for the use of this biomarker in CKD diagnostics. Among the other highly significant protein markers are insulin-like growth factor-binding protein 6, neuroblastoma suppressor of tumorigenicity 1, follistatin-related protein 3, trefoil factor 3, and beta-2 microglobulin. These proteins may indicate an imbalance in homeostasis across a variety of cellular processes, which may be underlying renal dysfunction. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, this study represents the most extensive characterization of the plasma proteome and its relation to GFR to date, and suggests the diagnostic and prognostic value of proteomics for CKD across all stages.

Proteomic analysis of rat plasma following transient focal cerebral ischemia.

AIM: This study aimed to identify plasma protein changes in a rat model of ischemic stroke using a proteomic approach. MATERIALS & METHODS: Four male Sprague-Dawley rats (3-6 months old) were subjected to 90 min of left middle cerebral artery occlusion under anesthesia with 1.5% isoflurane in O(2)/air followed by 24-h reperfusion. Blood samples (~100 µl) were collected at baseline, at the end of 90-min middle cerebral artery occlusion and at 24-h postreperfusion. Brain injuries were assessed by MRI at 24-h postreperfusion. Quantitative comparison of global plasma protein expression was performed using 2D differential in-gel electrophoresis. Differentially expressed protein spots were identified using peptide sequencing tandem mass spectrometry. RESULTS: These rats had clear brain infarction in the left hemisphere detected by MRI. Thirty-three protein spots of plasma samples were differentially expressed following focal cerebral ischemia/reperfusion. These protein spots belonged to eight proteins. Six of them (α2-macroglobulin, complement C3, inter-α- trypsin inhibitor heavy chain H3, serum albumin, haptoglobin and transthyretin), which are a class of acute-phase proteins, changed significantly. CONCLUSION: This study describes the responses of young rats to focal cerebral ischemia and suggests that future studies should use aged animals to better mimic the clinical ischemic stroke setting.